Description (Applicant Abstract): Is arterial oxygen content (CaO2) a critical and universal signal transduction pathway for oxygen sensing in humans? In a recant study by the applicant (Am J Physiol: Heart Circ Physiol 276: H1-HS, 1999), CaO2 was shown to have marked vasodilatory influence over blood flow measured in the periphery (leg) and centrally (cardiac output). The influence of CaO2 on vasodilatation was independent of the level of PaO2. Animal studies have reported similar findings in the cerebral circulation. This new finding may provide an important insight into the regulation of blood flow in exercising humans and raises several questions: Is CaO2 a universal oxygen sensor? Do many vascular beds react to changes in CaO2, but are impervious to changes in PaO2? What are the mechanisms of CaO2's action? The findings also suggest a link of the vasodilatory effects of CaO2 to the hemoglobin concentration since the major distinguishing physical difference between content and tension is the concentration of hemoglobin available to transport oxygen. Recent work has shown an important circulatory control role for hemoglobin as a nitric oxide scavenger. It is a small but important jump from the NO-linked vasodilatory behavior of hemoglobin to the effects observed for CaO2. If hemoglobin is not responsible, other factors such as prostaglandin concentration or red cell ATP-release could account for the observed CaO2-linked vasodilatory effects. The overall goal of the project is to determine if CaO2 is an oxygen-sensing pathway universal in human vascular beds. Therefore, physiological alterations of CaO2 and PaO2 will be coupled to noninvasive Doppler measurements in several conduit vessels to major vascular beds. The proposed study is designed to address three specific aims: 1) Can CaO2 be altered by carbon monoxide administration to yield the same results as seen with isovolemic hemodilution (as used in previous study)?; 2) Is a drop of CaO2 a universal signal for vasodilation in vascular beds amenable to study by non-invasive Doppler flowmetry?; and 3) What is the mechanism of action of altered CaO2? The findings will have broad implications for our understanding of the basic mechanisms underlying vascular control during rest and exercise.